Aortic stenosis is the most common cause of valvular heart disease and calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. There is currently no medical therapy, except for invasive valve replacement in symptomatic patients, for CAVD. This is mainly due to poor understanding of pathophysiology, in part due to lack of appropriate animal models, and lack of appropriate tools for risk stratification and tracking the effect of interventions in vivo. Beside traditional risk factors, age, gender, tobacco use, hypercholesterolemia, and hypertension, genetic background is an important determinant of CAVD. The effect of genetic background is best recognized in bicuspid aortic valve (BAV), the major cause of advanced CAVD and aortic stenosis in younger subjects. There is ongoing debate on whether hemodynamic alterations, genetic and cellular factors, or both lead to early development of CAVD in BAV. Valvular interstitial cell transformation, extracellular matrix remodeling (including fibrosis) and calcification are pathologic hallmarks of CAVD and play a central role in its pathogenesis. Several signaling pathways (e.g., Notch) which regulate bone formation are implicated in the pathogenesis of CAVD, and could potentially serve as targets for therapeutic interventions aimed at slowing down the progression of the disease. Endothelial and smooth muscle neuropilin-like protein (ESDN) is a marker of vascular remodeling and regulator of growth factor signaling in vascular cells. Interestingly, there is a high incidence of BAV (~50%) in Esdn-/- animals, and in preliminary studies we have observed spontaneous development of CAVD in aged Esdn-/- mice. These findings will be leveraged to address the aforementioned gaps in CAVD pathobiology and imaging, by investigating the role of the neuropilin-like protein, ESDN in experimental calcific aortic valve disease, and to examine the interplay between leaflet numbers, modifiable risk factors and genetic background in CAVD, while establishing novel molecular imaging techniques for tracking the effect of interventions and prediction of outcome in CAVD. These studies will lead to better understating of CAVD pathophysiology and potentially novel therapeutic targets to mitigate CAVD progression. In parallel, they will establish novel molecular imaging tools for risk stratification in CAVD with high potential for clinical translation.